I think low-dose Fluvoxamine could be worth exploring for this reason. It's not just an SSRI in this case. At low doses, it may not be much of an SSRI at all.
I agree. Good point.
In wondering whether Fluvoxamine is the only sigma-1 agonist, I found this study:
Allosteric Modulators of Sigma-1 Receptor: A Review (2019) [
10.3389/fphar.2019.00223]
I generally prefer reversible allosteric modulators over agonists because it normally gives the metabolism better chances to adapt with lower signaling variance and with reduced risks for dependence. It's possible that Fluvoxamine is also a modulator, I'm not entirely sure. Sometimes, modulators are also termed "agonists" or "antagonists" even though this isn't technically correct. It depends on how they measure the signaling. Specific human metabolite agonist antibodies are usually used to verify if it's an agonistic or positive-allosteric mechanism. Without this kind of control, they can't tell the difference.
Nevertheless, they also list fenfluramine, another SSRI, as a putative positive allosteric modulator. So there might be even more unidentified SSRIs. They all have the serotonin issue, of course.
They also list various drug candidates I've never heard of and I doubt are available or affordable. Among them, SKF-83,959 sounds like a promising candidate due to its combined effects on dopamine receptors.
Fortunately, there is one non-SSRI drug that could be repurposed, namely Phenytoin. Phenytoin is an anticonvulsant that is used against seizures, e.g. in epilepsy patients. It's an inhibitor of Na+ and Ca+ Voltage-gated channels, which coincidentally is consistent with CFS/ME pathology. It blocks sodium influx, probably by the same mechanism. This is also consistent with CFS/ME pathology in that sodium pumps oversaturate cells with sodium and desaturate them from potassium. Hence, phenytoin might also have protective functions on the heart. This mechanism might be shared by all sigma-1 modulators since sigma-1 is involved in the regulation of sodium channels [
10.1152/ajpcell.00431.2008]. According to this study, sigma-1 receptors are also abundant in the heart.
Sigma-1 is also very abundant in the brain, of course. But not so much in the liver and other organs, I suppose, because most in vitro studies with these tissues couldn't find any significant effect.
Phenytoin is a prescription drug just like any SSRIs, but it's quite cheap. It might also be indicated if CFS/ME patients have any history of seizures. I have a history of seizures. It's also indicated for certain kind of pain syndromes. Since most CFS/ME patients don't have epilepsy and the default dosage is adjusted for this, lower doses are most likely more helpful in order to avoid risks and side effects. Low-dose phenytoin has been successfully tried in one autism case so far [
10.1186/1752-1947-9-8].
By the way, unlike valproic acid, phenytoin apparently doesn't inhibit HDACs [
0.1111/j.0013-9580.2004.00104.x]. So, phenytoin can not trigger viral reactivations. It's unclear if valproic acid interacts with sigma-1 as well.
